Implementing New Technologies in Bioprocessing Howard L. Levine, Ph.D.

Transcription

1 Implementing New Technologies in Bioprocessing Howard L. Levine, Ph.D. Presented at: AGC Biologics 2018 Global CMO Consultant Summit September 10-13, 2018 Seattle, WA BioProcess Technology Consultants, Inc.

2 Biopharmaceuticals represent approximately 15% of the pharmaceutical market Market Continues to Grow Biopharmaceutical product sales in 2016 were $169 Billion CAGR was 21%; slowing slightly in recent years 2016 growth 10% over 2015 Approximately 33% of approved products are monoclonal antibody products Top 6 selling antibody products had 2016 sales of $53B Of the over 1,000 biopharmaceutical products in development, ~70% are monoclonal antibodies Nearly 75% of the product pipeline is produced in mammalian cell culture 2

3 Sales of Top 10 Products >$110 Billion Sales 2007 ($B) Product Rank Product Sales 2017 ($B) 5.28 Enbrel 1 Humira Remicade 2 Enbrel Rituxan/MabThera (EU) 3 Rituxan/MabThera (EU) Herceptin 4 Remicade Aranesp 5 Herceptin Avastin 6 Avastin Humira 7 Lantus/Toujeo (EU) Neulasta/Neupopeg (EU) 8 Eylea Procrit 9 Opdivo Lantus 10 Neulasta/Neupopeg (EU) Total of 98 products All Others Total of 211 products Total of 108 products Total Total of 221 products

4 Pace of antibody approvals accelerated in 2017 and continues at a higher pace in 2018 Ten new Mabs approved in Kaplon and Reichert, MABS 2018, VOL. 10, NO. 2,

5 Demand will Steadily Increase Bulk Product Requirements Total product requirements of 2017 almost 19 metric tons will increase to approximately 43 metric tons by 2022 Cell Culture Volume Requirements Over 2.1 million liters of cell culture capacity required in 2017 to meet product demand growing to nearly 3.8 million liters in 2022 Approximately 50% of capacity demand will be for out-sourced capacity 5

6 Capacity Supply Continues to Grow Current landscape for mammalian cell culture manufacturing includes almost 4 million liters of installed capacity Capacity divided among 137 companies with 201 separate manufacturing facilities worldwide By 2022, the industry will add approximately 1.8 million liters of new capacity bringing total global capacity to approximately 5.6 million liters. 6

7 Future needs Perspectives on Innovation Large amounts of drug substance and small amounts! Lower pricing of biologics Better quality control of drugs Will increased capacity alone solve all of this? Probably not! What are we, as an industry, to do? 7

8 Implementing New Technologies Moore s Law: In 1965, Intel co-founder Gordon Moore predicted transistor counts in integrated circuits and computing capacities and speeds would double every two years Moore s Law Corollary for Cell Culture Titers have increased from 100 milligrams per liter in the early 1980s at a cost of $10,000/gram to 5 grams per liter today at costs as low as $100/gram Can we improve manufacturing? What can we do? Increase facility output Improve process efficency and economics Implement advanced process controls 8

9 Implementing New Technologies Moore s Law: In 1965, Intel co-founder Gordon Moore predicted transistor counts in integrated circuits and computing capacities and speeds would double every two years Moore s Law Corollary for Cell Culture Titers have increased from 100 milligrams per liter in the early 1980s at a cost of $10,000/gram to 5 grams per liter today at costs as low as $100/gram Can we improve manufacturing? What can we do? Increase facility output Improve process efficency and economics Implement advanced process controls 9

10 FDA guidance on Process Analytical Technology (PAT) issued in 2004 Measuring, Monitoring, and Controlling Bioprocesses Encouraged use of innovative tools and technologies to increase understanding and control of manufacturing processes Application of such tools and technologies is still a work in progress but progress is being made For upstream processes, Advanced Process Control includes probes to measure parameters such as viable biomass, glucose, lactate and ammonia Bio-capacitance probes NIR Raman 2D-fluorescence ph Combined with uni- and multi-variate data analysis this enables construction of modules such things as nutrient feed or glucose where the additions are adapted to the exact needs in the ongoing cell culture 10

11 Building an Automatic Control Strategy 11 Automatic control strategy using exclusively real-time available signals Constants (safety factors and the biomass model) were defined a priori PLS: Partial Least Squares regression GLC: Glucose Concentration Konakovsky V, et al. Bioengineering 2016 Jan 11;3(1). pii: E5. doi: /bioengineering MVDA of historical data used to build biomass model Bio-capacitance, ph, glucose measured Feed rate calculated with transferable biomass model based on capacitance Changes nutrient flow stoichiometrically in real time Results in extremely stable, low glucose levels, very robust ph profiles without acid/base interventions, and a metabolic state in which lactic acid is consumed instead of being produced Method allowed transfer of the desired metabolic state from pilot scale to manufacturing without change in line with PAT and QbD for improving process robustness and reliability

12 Since its formation, FDA was plagued by a culture of Enforcement First that stymied innovation Continuous Processing In 2004, the Pharmaceutical cgmps for the Twenty First Century: A risk-based Approach guidance opened the door for more innovative approaches to manufacturing Right now, manufacturing experts from the 1950s would easily recognize the pharmaceutical manufacturing processes of today. It is predicted that manufacturing will change in the next 25 years as current manufacturing practices are abandoned in favor of cleaner, flexible, more efficient continuous manufacturing. Traditional batch processing Dr. Janet Woodcock, AAPS Annual Meeting, October 2011 First small molecule continuous manufacturing process for Vertex s Orkambi, drug product drug product was approved by FDA in 2015 (1) 12

13 Imagine if You could purify 1 kg of monoclonal antibody using less than 1 L of Protein A media, flow rates of >200 ml/min, and a total processing time of less than one week Continuous Processing This is the potential for continuous processing in biopharmaceutical manufacturing Smaller facilities Less capital and materials Faster and more predictable supply with improved process control 13

14 MoBiDiK and the Great White MAb Bayer s Modular, Biologics, Disposable, Konti system is a demonstration facility for continuous bioprocessing Upstream of MoBiDiK is batch, while the downstream is continuous 14 steps in downstream purification train Entire system is automated, there is no manual handling System can be built quickly (5 days for setup) Process run for four weeks System is highly complex Team diversity is key Risk Assessments are important 14

15 Our industry can (and has) adopted new technologies, but we are conservative and adoption cycles are lengthy Adoption of New Technology But the environment is changing, driving evolution Speed to clinic/market and capital efficiency are more important than ever Expectations for process understanding and control are increasing Regulators are receptive to approaches that can improve product quality and reproducibility Biosimilars and overall healthcare spending concerns are pressuring prices 15

16 We can fine tune our approach to improve performance Operational excellence initiatives Tweaking the platform particularly for antibodies What s stopping us? We must develop a varied and expanding toolbox incorporating novel technologies and approaches Creative facility and equipment concepts (SUTs; ballroom design) Process intensification (continuous; integrated unit ops) Real-time quality (PAT; real-time release) New and novel technologies for downstream processing These will enable future bioprocessing that may include Intensified upstream processes Advanced bioreactor clarification Improved chromatographic and non-chromatographic separations Advanced process controls and PAT Continuous processing 16

17 We need a few unreasonable men: To make progress We must think outside the box: We must share knowledge: 17

18 Thank You! Howard L. Levine, Ph.D. BioProcess Technology Consultants, Inc. 12 Gill Street, Suite 5450 Woburn, MA